Process for preparation of alpha tocopherol



United States Patent O i 2,998,430 PROCESS FOR PREPARATION OF ALPHATOCOPHEROL Frank J. Sevigne, Tarrytown, N.Y., assignor to Collett-- WeekCorporation, Ossining, N.Y., a corporation of New York No Drawing. FiledSept. '26, 1958, Ser. No. 763,450 6 Claims. (Cl. 260-3455) 1 E activity,While non-alpha tocopherols, such as beta,

gamma and delta, have much lower activity. Since the non-alpha formspredominate in nature many attempts have been made to convert them tothe more biologically active alpha form. The non-alpha tocopherolsdiffer from the alpha only in that one or both methyl groups are missingfrom the 57 positions. Attempts at conversion in-the past have involvedthe direct methylation of the non-alpha tocopherols and have beenreasonably successful.

Accordingly, this invention provides a method for the conversion ofnon-alpha tocopherol compounds to the alpha form, which is characterizedby a sequence of steps comprising, first, oxidizing the compounds toquinone form and opening the chroman ring, thereupon haloalkylating thesaid compounds, in which step the quinone form is reduced, thenreclosing the ring to give the desired tocopherol. The process is thuscharacterized by the sequence and combination of steps involved in theprocess, all of which are carried out under very mild conditions, whichresult in minimum formation of impurities and side reactions, theprocess being further characterized by the smoothness and ease withwhich it takes place ineach step and the high yields obtained at eachstep in the operation.

The process of the present invention may be carried out with non-alphatocopherols in various forms. It may be carried out with the variouspure non-alpha tocopherols, i.e., ,8, 6, or it may be carried out withimpure mixtures of inert materials containing varying, even small,amounts of the tocopherols. For instance, it may be carried out with byproducts resulting from the refining of vegetable oils, for example, hotwell sludge from the steam refining of vegetable oils, soybean oil, cornoil, wheat germ oil, peanut oil, olive oil and the like, are sources ofthe deodorizer sludge. Wheat carries variable but significant amounts ofthe tocopherol compounds. It will be understood that the several stepsof the invention may be carried out in different ways with different rawmaterials and under modified conditions to suit the particular rawmaterial being processed.

, In summary, therefore, the process may be illustrated by the followingsequence of reactions.

Summary of equations as follows:

/CE2 R1 Ra Rs 110- on. a on: OH; on. CH3 w B2 s CH3 H CH3 CmHaa y H CH3CH3 R3 5 n H CH3 lFeGlainMeOH x H H H 2,98,43Q Patented Aug. 29, 1961 /C2 O 1 on,

OHO CwHas 1 I o@ '1 CH2 /CH 0: CH3 CH3 CH3 6 4 RF 5 e 0113 011201 on.

OHO CroHas R3 7 011. 01 CH3 on;

6 CHzCl 011201 OH; Zn+HOl x CHrCl 011201 CHzCl OHz CH2 "1 3 CH2 CHa HsC-OH HO CwHas ZnO1n+CHaCOOH +Zn HO CH2 O CmHss Tocopherol occursprincipally as a, 'y, 6 isomers in a large number of naturally occurringvegetable oils. Hence, a direct application of the process is in theconversion of 'y, 8 tocopherols to the biologically useful alpha form.

EXAMPLE I: CONVERSION OF B-TOCOPI-IEROL OXIDATION One-tenth (0.1) partof pure beta-tocopherol was dissolved in 5 parts of anhydrous methylalcohol. A solution containing 0.25 parts of FeCl -6H O in 5 parts ofmethyl alcohol was added dropwise over a period of fifteen minutes.Twenty (20) parts of distilled water were added and the mixture wasextracted with 20, 10 and 10 part portions of ethyl ether. The combinedether solutions were washed five times with 10 part portions ofdistilled water, dried with anhydrous sodium sulfate, filtered, and thesolvent distilled off under vacuum.

The reddish-yellow oil obtained was subjected to a second oxidationunder identical conditions. The oil was dissolved in 5 parts ofanhydrous methyl alcohol, a solution of FeCl (0.25 part FeCl .6H O in 5parts CH OH) was added drop-wise over a fifteen-minute period. Twenty(20) parts of distilled water were added and the mixture was extractedwith 20, l0 and 10 part portions of ethyl ether. The combined ethylether extracted was washed five times with 10 part portions of distilledwater, dried over Na SO filtered and the solvent removed under vacuum.The residue consisted of a red-yellow oil.

For the oxidation phase of the process anoxidation system or agenthaving about the oxidation potential of the ferric chloride solutions isdesired. It is essential in the process to oxidize to the quinone formand to leave 3 the chroman ring, but without causing degradation of theintermediate benzoquinone.

The following typical data summarize the course of the oxidationreaction carried out at room temperature:

(1) Oxidation at room temperature FeCl -cnc.=1 molar A=261 millimicrons.E=Extinction coefiicient U.V.

The only significance of the data is that the measurement may be used asa control and reaction time should be adjusted to maximize it. The datalisted above was obtained with 'y tocopherol but apply also to p, withminor variations.

(2) Chloromethylation and reduction Eight hundredths part of theoxidation product was dissolved in 4 parts of ethyl ether. Two tenths(0.2) part of concentrated hydrochloric acid and 0.1 part offormaldehyde was added and the mixture stirred under nitrogen for threehours. Two tenths (0.2) part of concentrated hydrochloric acid was addedand then 0.25 part of zinc dust was slowly added over a thirty-minuteperiod. The mixture was then stirred for an additional two-hour period.The mixture was then extracted three times with 10 part portions ofethyl ether. The ether extracts were combined, washed six times withpart portions of distilled water, dried over Na SO filtered, and thesolvent removed under vacuum.

(3 Cyclization Six hundredths part of the reduced chloromethylatedproduct was dissolved in 5 parts of glacial acetic acid. Five tenths(0.5) part of hydrobromic acid and 0.2 part of zinc dust were added andthe mixture refluxed for ten minutes under nitrogen. After diluting with40 parts of distilled water, the acid solution was extracted three timeswith 30 part portions of ethyl ether. The combined ether extracts werewashed twice with part portions of 2N Na CO solution and then six timeswith 10 part portions of distilled water. The ether solution was driedover Na SO filtered and the solvent removed under vacuum. The residueconsisted of a pale yellow oil containing 72 percent total tocopherolaccording to assay. The alpha tocopherol content of the oil was 53percent as indicated by chemical assay according to the method of Quaife(J. Biol. Chem, 175, 605, 1948).

EXAMPLE II: CONVERSION OF a-T'ICOPHEROL (1) Oxidation One-tenth (0.1)part of pure a-tocopherol was dissolved in 5 parts methyl alcohol andtwice oxidized with a 10 mole FeCl -methyl alcohol solution duringconsecutive periods of ten minutes in the manner of Example I. Theresidue obtained was a yellow-red oil of fi-tocopheryl quinone.

(2) Chloromethylation The quinone was dissolved in 5 parts of ether andvigorously stirred with 0.5 part concentrated hydrochloric acid and 0.2part of formaldehyde for two hours under nitrogen.

(3 Reduction For the reduction 0.2 part concentrated hydrochloric acidwas added and then 0.5 part Zn-dust with stirring over a ten-minuteperiod. The reaction was continued for two hours; 5 parts ether wereadded and the ether layer decanted from the acid solution and the Znresidue. The ether solution was washed ten times with 5 part portions ofwater, dried over Na SO filtered and evaporated under vacuum. Theproduct obtained was a pale yellow oil.

(4) Cyclization 0.090 part hydroquinone was dissolved in 2 parts dioxaneand refluxed for 5 /2 hours under N with 0.2 part stannous chloride and0.15 part concentrated hydrochloric acid. The light reddish solution wasdiluted with 10 parts water and extracted three times with 10 partsether. The ether solutions were washed six times with 10 parts of water,dried over Na SO filtered and the solvent evaporated under vacuum. Theresidue obtained was a yellow oil.

EXAMPLE III: METHYLATION OF GAMMA- TOCOPHEROL (1 Oxidation One andeleven hundredths (1.011) parts gamma-tocopherol were dissolved in 23parts ethyl alcohol with a solution of 2.5 grams FeCl .6I-I O in 20parts ethyl alcohol added, with stirring, for ten minutes. Then thereaction was continued with refluxing for five minutes. The colorlesssolution quickly became red. After cooling, 150 parts of water wereadded and the oxidized organic part was extracted with 60, 40 and 40parts ethyl ether. The combined ethyl ether solutions were washed fivetimes with 60 parts water, dried over Na SO and the solvent distilledoflf under vacuum. The residue obtained was a red oil 1:017 parts.

(2) Chloromethylation One (1.00) part quinone was dissolved in 20 partsether and vigorously stirred under nitrogen with 2 parts concentratedhydrochloric acid and 1 part of formaldehyde for one hour. After afurther addition of 0.3 part of formaldehyde the reaction was continuedfor two hours. During the reaction time the color turned from red toyellowred.

(3 Reduction To the solution thus obtained were added 2 partsconcentrated hydrochloric acid and then during 25 minutes, 2.5 partszinc-dust. The reduction was stopped after 2 /2 hours. The red colorchanged to colorless within five minutes. Thirty (30) parts of etherwere added, shaken well and then decanted from the acid solution. Thiswas repeated twice. The combined ether solutions were washed eight timeswith 30 parts of water, dried over Na SO filtered, and evaporated undervacuum. The residue obtained was a pale yellow oil, 0.933 part (yield 90percent).

' (4 Cyclization 0.920 part of the above hydroquinone was dissolved in10 parts dioxane. One (1) gram SnCl and 0.7 part concentratedhydrochloric acid were added and the mixture was heated at reflux forsix hours. The color turned yellow-red. After adding 30 parts of water,this solution was extracted three times with 30 parts ether. The organicphase was washed six times with 40 parts water, then dried over Na SOfiltered, and stored overnight in an icebox. After evaporation undervacuum a light, yellowish oil remained, 1.12 parts (yield 92 percent).

EXAMPLE IV: CONVERSION OF SOYBEAN OIL SLUD GE Raw material obtained fromsoybean oil sludge produced in the steam treatment of soybean oil wasused in the process, as described in Examples I-l'II. It contained arandom mixture of a, 'y, 5 tocopherols in total concentration of 5percent. The sludge was saponified with alcoholic potassium hydroxide,and the unsaponifiable and frozen to separate the sterols to give atocopherol concentrate having the following characteristics:

Percent Alpha Tocopherol 4.0 Non-alpha Tocopherol 36.5

(I Oxidation with FeCl to tocopheryl quinone (2) Chloromethylation Thepetroleum ether solution was concentrated in vacuo to about 250 parts;50 parts of concentrated hydrochloric acid and 25 parts of formaldehydewere added and the mixture stirred for three hours under nitrogen.

(3) Reduction with Zn dust and concentrated HCZ To the above mixturewere added with stirring, 50 parts of concentrated hydrochloric acid and50 parts of Zn dust, the latter being added in small increments over aperiod of two hours. The petroleum ether layer was separated, washedfive times with equal portions of water,

dried with anhydrous sodium sulfate, filtered, and the solvent removedunder vacuum on a steam bath. The residue consisted of a light orangeoil (45.1) grams.

(4) Ring closure with acetic acid, ZnCl and Zn dust To the light orangeoil, 45.1 parts was added a mixture of 200 parts 80 percent acetic acid,20 parts of ZnCl and 2 parts of zinc dust. The solution was heated to 60C., and maintained at that temperature or six hours with constantstirring. The mixture was cooled to room temperature, transferred to aseparatory funnel, diluted with water (2,000 parts) and extracted threetimes with 300 part portions of petroleum ether. The petroleum etherlayer was separated, washed eight times with 100 part portions of waterand dried with sodium sulfate. The filtered petroleum ether solution wasevaporated to dryness in vacuo on a steam bath. The residue consisted ofa yellow oil (40.2 grams), having the following analysis:

Total Tocopherol a Non a Methylated material, percent"... 33. 0 27. 4 5.6

In typical routine plant operation, yields are easily obtained asfollows:

The examples have been stated in quite specific terms as detailedinstructions for the preparation of the alpha tocopherol. This isbecause they represent actual plant practice and as such a usefulapproximation of ideal quantitative conditions. It is to be understood,of course, that in any one of the examples, the solvents used, precisetemperature levels and extracting materials used may be varied withoutmaterially departing from the sequence of operations in the process.When no temperature is specified, the reaction was conducted at ambienttemperature.

For example, in the conversion of the tocopherol compound in the initialoxidation step in any one of the Examples 1, 2 and 3, the solvent may beethyl, propyl, or butyl alcohol. It is merely necessary that it besufliciently indiflerent to the oxidation conditions to be unaffected 6r in the reaction. Similarly, in place of preferred ferric chloridesolution, a gold chloride or other metal salt oxidizing agent havingabout that oxidation potential will be useful. Since the purpose of theoxidation step is merely to open the chroman ring, the conditions ofreaction should be directed to that result.

In the extraction of the reaction product, ethyl ether is used, becausethat has the advantage of being a good solvent immiscible with water andefiective for the purpose. However, other ethers, such as methyethylether may be used, because the basic requirement is high solventcapacity for the tocopherol quinone.

In the chloromethylation and reduction phase of the operation, thesolvent used was ethyl ether in the several examples, but it is to beunderstood, of course, that any solvent for the reactants would beuseful. Here methyl ether or methylethyl ether will serve the purpose.In the actual chloromethylation which is conducted, the formaldehyde andhydrogen chloride may be used in the gaseous form, or the formaldehydemay be used in the solid paraldehyde form. Similarly, the reducing agentis zinc dust and hydrochloric acid because it is a convenient one, butactually any pair of reactants, for example, a zinc amalgam is suitablefor forming the nascent hydrogen.

In the cyclization step of reaction, glacial acid hydrochloric acid andzinc dust were used. The reactions were specific but it is to beunderstood that any reactants usable for the purpose of closing thechroman ring might be used.

Although the invention has been described with reference to a limitednumber of examples, it is to be understood variations thereof may bepracticed without departing from the spirit or scope of the invention.

What is claimed is:

1. The process of converting a tocopherol selected from the groupconsisting of beta, gamma, and delta tocopherol and mixtures thereof tothe alpha tocopherol form, comprising, oxidizing a material containingsaid tocopherol under mild oxidizing conditions whereby the chroman ringopens forming a tocopheryl para quinone, chloromethylating said paraquinone with formaldehyde and hydrogen chloride at about ambienttemperature, whereby any hydrogen atoms present on the phenyl ring arereplaced with chloromethyl radicals, reducing said compound with zincand hydrochloric acid whereby the chloromethyl radicals are converted tomethyl radicals, acidifying the mixture and thereby closing'the ring ofsaid compound whereby alpha tocopherol is produced from said tocopherylquinones.

2. The process of claim 1 wherein the oxidation step is conducted byreacting the tocopherol with ferric chloride.

3. The process of claim 1 wherein the chloromethylation step isconducted by reacting the quinone with a formaldehyde yielding materialand hydrochloric acid.

4. The process of claim 1 wherein the reduction step is conducted byreacting the chloromethylated product with zinc dust and hydrochloricacid.

5. The process of claim 1 wherein the cyclization step is conducted withstannous chloride.

6. The process of claim 1 wherein the cyclization step is conducted withzinc chloride.

References Cited in the file of this patent UNITED STATES PATENTS2,486,539 Weisler Nov. 1, 1949 2,486,542 Weisler et al. Nov. 1, 19492,843,604 Hawks July 15, 1958 OTHER REFERENCES John et al.: ChemicalAbstracts, vol. 33, page 2896 (1939).

Dedication 2,998,430. F"an7a J. Se'uz'gne, Tarrytown, N .Y. PROCESS FORPREPARA- TION OF ALPHA TOCOPHEROL. Patent dated Aug. 29, 1961.Dedicatipn filed May 20, 1976, by the as

1. THE PROCESS OF CONVERTING A TOCOPHEROL SELECTED FROM THE GROUPCONSISTING OF BETA, GAMMA, AND DELTA TOCOPHEROL AND MIXTURES THEREOF TOTHE ALPHA TOCOPHEROL FORM, COMPRISING, OXIDIZING A MATERIAL CONTAININGSAID TOCOPHEROL UNDER MILD OXIDIZING CONDITIONS WHEREBY THE CHROMAN RINGOPENS FORMING A TOCOPHERYL PARA QUINONE, CHLOROMTHYLATING SAID PARAQUINONE WITH FORMALDEYDE AND HYDROGEN CHLORIDE AT ABOUT AMBIENTTEMPERATURE, WHEREBY ANY HYDROGEN ATOMS PRESENT ON THE PHENYL RING AREREPLACED WITH CHLOROMETHYL RADICALS, REDUCING SAID COMPOUND WITH ZINCAND HYDROCHLORIC ACID WHEREBY THE CHLOROMETHYL RADICALS ARE CONVERTED TOMETHYL RADICALS, ACIDIFYING THE MIXTURE AND THEREBY CLOSING THE RING OFSAID COMPOUND WHEREBY ALPHA TOCOPHEROL IS PRODUCED FROM SAID TOCOPHERYLQUINONES.